Overall SUMMARY Dominantly inherited Alzheimer's disease (AD) is an attractive model for study because the responsible mutations have known biochemical consequences that underlie the pathological basis of the disorder. The opportunity to determine the sequence of imaging and biomarker changes in asymptomatic gene carriers who are destined to develop AD may reveal critical information about the pathobiological cascade that culminates in symptomatic disease. Because the clinical and pathological phenotypes of autosomal dominant AD (ADAD) appear similar to those for the far more common late onset ?sporadic? AD, the nature and sequence of brain changes in ADAD are relevant for late-onset AD (LOAD). Promising therapeutic agents for ADAD may also apply to LOAD. However, a longitudinal study of a large cohort of individuals with ADAD required innovative approaches, as ADAD mutations are rare and families are geographically dispersed worldwide. In its initial funding period beginning in 2008, the Dominantly Inherited Alzheimer Network (DIAN) established an international, multicenter registry of individuals (gene carriers and noncarriers; asymptomatic and symptomatic) who are at risk of carrying a known causative mutation for AD in the amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes. Individuals are evaluated upon enrollment in DIAN and longitudinally thereafter with standard instruments including the Uniform Data Set of the Alzheimer's Disease Centers and protocols developed by the Alzheimer's Disease Neuroimaging Initiative (ADNI) for structural, functional, amyloid imaging , biological fluids (blood; CSF), and histopathological examination of cerebral tissue in individuals who come to autopsy. DIAN's major hypotheses include: 1) AD biomarker changes in mutation carriers occur many years before symptomatic AD, supporting the concept of preclinical AD; 2) initial biomarker changes in the preclinical stage of ADAD will involve A?42, followed by neurodegeneration and subsequent cognitive decline; and 3) the clinical and neuropathological phenotypes of ADAD will be similar to, but not identical with, those of LOAD. Although cross-sectional data obtained in preceding budget periods provided support for each of these hypotheses, we are increasingly finding that longitudinal data provides more accurate and precise information on biomarker changes. Hence, this application emphasizes longitudinal data collection and analyses. This renewal application continues to address the original DIAN hypotheses and aims, such as maintenance of the established international DIAN registry of individuals. Importantly, three new scientific initiatives are integrated to investigate common ADAD mechanisms of A? pathogenesis (Project 1), tau pathophysiology (Project 2), and novel mechanisms of neurodegeneration and neuroinflammation (Project 3). We also propose to harmonize DIAN with the independently funded DIAN Trials Unit (TU) and Expanded Registry (EXR) to enable data sharing across all three studies.